The Role of Mitochondrial ATP-Binding Cassette Transporter ABCB6 in Metabolism and Energy Balance

• Main Author: Tessman, Robert T
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2019
• Subjects: Endocrinology; Genetics; Toxicology
• ISBN: 9781085625708; 1085625702

Obesity and the associated health risks represent a world-wide health and financial crisis. Lack of physical activity combined with excessive caloric intake are the root cause of the problem. Despite the increased advocation for healthy lifestyle choices, the trend has yet to reverse and indeed, seems to be on the rise especially among pre-teens and adolescents, a constituent that had not been previously part of the obesity epidemic.Mitochondria are the “fuel-burners” of the body and like other combustion devices, become inefficient in the context of fuel surplus. Moreover, with chronic over-feeding, the physiological mechanisms that regulate energy balance become permanently dysfunctional leading to the progression of pathologies such as Type II diabetes and cardiovascular disease.Medical and scientific evidence confirms that mitochondria are integral to the responses necessary to adapt to over-nutrition. However, success in mitochondria-based therapies has been extremely limited in the context of metabolic diseases. Our knowledge of the regulation of mitochondrial function, dynamics, signaling, and transport processes in different tissues and organ systems is extremely limited and this knowledge gap is a serious impediment to progress toward targeting mitochondria for treatment of metabolic diseases.In this study, we successfully genetically manipulated the expression of mitochondrial transporter ABCB6. The physiological function of this transporter is unknown but non-functional mutations of this protein have been linked to several heritable human diseases.This study establishes that ABCB6 plays a role in the maintenance of energy homeostasis. Whole-body Abcb6 knockout adult male and female mice have increased body mass with no increases in food consumption. Increased body mass is due to increased adiposity. ABCB6 deficiency results in steatosis, glucose intolerance, insulin resistance, and lower energy expenditure. Exposure to high-fat diet exacerbates these metabolic derangements.Genetically targeting ABCB6 expression specifically in liver results in disruption of whole-body energy metabolism as well with a loss of metabolic flexibility. Loss of hepatic ABCB6 results in fragmented mitochondria while overexpression leads to mitochondrial elongation, dysregulating dynamic mitochondrial functional responses to energy status. In this liver-specific model, hepatic metabolites are significantly altered with either ABCB6 knockdown or overexpression. Metabolites that have a profound impact on energy metabolism such as bile acids, amino acids, and phospholipids were significantly altered in this model.Interestingly, we discovered that ABCB6 expression is responsive to nutrient status and circadian patterns. ABCB6 expression is upregulated in the fasted state and rapidly downregulated in response to feeding. Also, ABCB6 expression is reduced in cases of chronic over-nutrition such as, diet and genetic mouse models of obesity as well as in clinically obese humans. These findings suggest that ABCB6 acts as a nutrient sensor and mediates a homeostatic response through dynamic mitochondrial changes in form and function.